Search

The present review shall familiarize the readers with the role of renin-angiotensin aldosterone system (RAAS), which regulates blood pressure, electrolyte and fluid homeostasis. The local RAAS operates in an autocrine, paracrine and/or intracrine manner and exhibits multiple physiological effects at the cellular level. In addition to local RAAS, there exists a complete pancreatic RAAS which has multi-facet role in diabetes and cardiovascular diseases. Aldosterone is known to mediate hyperinsulinemia, hypertension, cardiac failure and myocardial fibrosis while angiotensin II mediates diabetes, endothelial dysfunction, vascular inflammation, hypertrophy and remodeling. As the understanding of this biology of RAAS increases, it serves to exploit this for the pharmacotherapy of diabetes and cardiovascular diseases., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The renin–angiotensin system (RAS) plays a critical role in the pathogenesis of many types of cardiovascular diseases including cardiomyopathy, valvular heart disease, aneurysms, stroke, coronary artery disease and vascular injury. Besides the classical regulatory effects on blood pressure and sodium homoeostasis, the RAS is involved in the regulation of contractility and remodelling of the vessel wall. Numerous studies have shown beneficial effect of inhibition of this system in the pathogenesis of cardiovascular diseases. However, dysregulation and overexpression of the RAS, through different molecular mechanisms, also induces, the initiation of vascular damage. The key effector peptide of the RAS, angiotensin II (Ang II) promotes cell proliferation, apoptosis, fibrosis, oxidative stress and inflammation, processes known to contribute to remodelling of the vasculature. In this review, we focus on the components that are under the influence of the RAS and contribute to the development and progression of vascular disease; extracellular matrix defects, atherosclerosis and ageing. Furthermore, the beneficial therapeutic effects of inhibition of the RAS on the vasculature are discussed, as well as the need for additive effects on top of RAS inhibition. [ABSTRACT FROM AUTHOR]

Abstract: Treatment of Wistar rats for 7 days with 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), an antagonist of adenosine receptors, induces long-lasting hypertension associated with marked changes in vascular structure and reactivity and renin–angiotensin system activation. This study aimed at evaluating the role of oxidative stress in the development of DPSPX-induced hypertension and also at identifying the relative contribution of superoxide radical (O2 •−) vs hydrogen peroxide (H2O2). Vascular and systemic prooxidant/antioxidant status was evaluated in sham (saline, i.p., 7 days) and DPSPX (90 μg/kg/h, i.p., 7 days)-treated rats. Systolic blood pressure was determined by invasive and non-invasive methods. The activity of vascular NADPH oxidase, superoxide dismutase (SOD), catalase and glutathione peroxidase was assayed by fluorometric/spectrophotometric methods. H2O2 levels were measured using an Amplex Red Hydrogen Peroxide kit. Plasma thiobarbituric acid reactive substances and plasma antioxidant capacity were also measured. In addition we tested the effects of antioxidants or inhibitors of reactive oxygen species generation on blood pressure, vascular hyperplasia and oxidative stress parameters. DPSPX-hypertensive rats showed increased activity of vascular NADPH oxidase, SOD, catalase and glutathione peroxidase, as well as increased H2O2 generation. DPSPX-hypertensive rats also had increased plasma lipid peroxidation and decreased plasma antioxidant capacity. Treatment with apocynin (1.5 mmol/l, per os, 14 days), or with polyethylene glycol (PEG)-catalase (10,000 U/kg/day, i.p., 8 days), prevented the DPSPX-induced effects on blood pressure, vascular structure and H2O2 levels. Tempol (3 mmol/l, per os, 14 days) failed to inhibit these changes, unless PEG-catalase was co-administered. It is concluded that O2 •− generation with subsequent formation of H2O2 plays a major role in the development of DPSPX-induced hypertension. [Copyright &y& Elsevier]

Polymorphisms of the renin–angiotensin system are associated with cardiovascular disorders, possibly as a consequence of increased brain angiotensin II activity. Within the brain, angiotensin controls blood pressure, fluid balance and hormone secretion; it also influences behaviour: reduction of central angiotensin function has both antidepressant-like and axiolytic-like actions. Evidence concerning the role of the renin–angiotensin system in learning and memory is contradictory, although more studies support the proposal that angiotensin reduces cognitive function. Studies of renin–angiotensin system genotype and psychological status have suggested an association between the angiotensin-converting enzyme deletion allele and age related cognitive decline, but a greater prevalence of the insertion allele in Alzheimer''s disease. The deletion allele has also been associated with depressive illness, as has the M allele of the angiotensinogen gene although other studies have failed to replicate these findings. The role of the brain renin–angiotensin system in human psychopathology remains to be fully explored. [Copyright &y& Elsevier]

Type 2 diabetes mellitus is an independent risk factor for renal impairment, developing in due course to end-stage kidney disease (ESKD). Such progressive renal damage is related to an increased predisposition to cardiovascular events and mortality. Even with intensive glycemic control and use of nephro-protective renin angiotensin system (RAS) blockers, rise in the worldwide prevalence of diabetic kidney disease remains tenacious. Identifying drugs with potential to halt progressive renal damage is the pressing priority at present. Sodium glucose cotransporter 2 (SGLT2) inhibitors, by virtue of their glucose-lowering and additional pleotropic effects, such as weight reduction, blood pressure lowering, anti-inflammatory, anti-fibrotic effects etc. are postulated to affect systemic and intrarenal hemodynamic mechanisms in a favorable manner which ultimately contribute to beneficial processes in the kidney. The promising reno-protective efficacy of these drugs is further highlighted by a reduction in development/progression of albuminuria and stabilization of renal function associated with their use. In particular, recent cardiovascular and kidney disease focused outcome trials have effectively demonstrated reduced rates of ESKD and other hard renal end-points, including doubling of serum creatinine, renal transplantation, death due to renal causes etc. with SGLT2 inhibitors. In this review, we dig further deep into the proposed reno-protective benefit furnished by this class of drugs by summarizing the evidence generated from clinical trials and large real-world studies. Current guideline recommendations and probability of reno-protection being influenced by factors, such as diabetic status, baseline renal function, RAS blockade is also explored to discuss their intended use in clinical settings. [ABSTRACT FROM AUTHOR]